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Origins and immunopathogenesis of autoimmune central nervous system disorders

Nature Reviews Neurology volume 19, pages 172–190 (2023)Cite this article

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Abstract

The field of autoimmune neurology is rapidly evolving, and recent discoveries have advanced our understanding of disease aetiologies. In this article, we review the key pathogenic mechanisms underlying the development of CNS autoimmunity. First, we review non-modifiable risk factors, such as age, sex and ethnicity, as well as genetic factors such as monogenic variants, common variants in vulnerability genes and emerging HLA associations. Second, we highlight how interactions between environmental factors and epigenetics can modify disease onset and severity. Third, we review possible disease mechanisms underlying triggers that are associated with the loss of immune tolerance with consequent recognition of self-antigens; these triggers include infections, tumours and immune-checkpoint inhibitor therapies. Fourth, we outline how advances in our understanding of the anatomy of lymphatic drainage and neuroimmune interfaces are challenging long-held notions of CNS immune privilege, with direct relevance to CNS autoimmunity, and how disruption of B cell and T cell tolerance and the passage of immune cells between the peripheral and intrathecal compartments have key roles in initiating disease activity. Last, we consider novel therapeutic approaches based on our knowledge of the immunopathogenesis of autoimmune CNS disorders.

Key points

  • The immunopathogenesis of autoimmune CNS disorders involves complex interactions among a number of contributing factors.

  • Non-modifiable risk factors, such as age, sex, ethnicity and genetics (including monogenic disorders, common variants and polymorphisms in vulnerability genes, and HLA associations), might help to determine an individual’s predisposition to neurological autoimmunity.

  • Interactions between epigenetic and environmental factors can modify disease onset and severity.

  • ‘Triggers’ for loss of immune tolerance, such as infections, neoplasms and iatrogenic drugs (for example, immune-checkpoint inhibitors), might precipitate neurological autoimmunity.

  • Disruption of B cell and T cell tolerance and the passage of immune cells from the peripheral circulation to the CNS have key roles in initiating disease activity.

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Fig. 1: The spectrum of autoimmune CNS disorders.
Fig. 2: Demographic associations in autoimmune CNS disorders.
Fig. 3: Immunopathogenic mechanisms that contribute to CNS autoimmunity.

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Authors and Affiliations

  1. Translational Neuroimmunology Group, Kids Neuroscience Centre, Children’s Hospital at Westmead, Sydney, New South Wales, Australia

    Sudarshini Ramanathan, Fabienne Brilot & Russell C. Dale

  2. Sydney Medical School, Faculty of Medicine and Health and Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia

    Sudarshini Ramanathan & Russell C. Dale

  3. Department of Neurology, Concord Hospital, Sydney, New South Wales, Australia

    Sudarshini Ramanathan

  4. School of Medical Science, Faculty of Medicine and Health and Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia

    Fabienne Brilot

  5. Oxford Autoimmune Neurology Group, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, UK

    Sarosh R. Irani

  6. TY Nelson Department of Paediatric Neurology, Children’s Hospital Westmead, Sydney, New South Wales, Australia

    Russell C. Dale

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  1. Sudarshini Ramanathan
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Contributions

S.R. and R.C.D. researched data for the article and wrote the article. All authors contributed substantially to discussion of the content, and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to Russell C. Dale.

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Competing interests

S.R. has received research funding from the National Health and Medical Research Council (NHMRC, Australia), the Petre Foundation, the Brain Foundation (Australia), the Royal Australasian College of Physicians, and the University of Sydney. She is supported by an NHMRC Investigator Grant (GNT2008339). She serves as a consultant on an advisory board for UCB and Limbic Neurology, and has been an invited speaker for Biogen, Excemed and Limbic Neurology. F.B. has received research funding from NSW Health, MS Australia, the NHMRC (Australia), the Medical Research Future Fund (Australia) and Novartis. She was on an advisory board for Novartis and Merck, and has been an invited speaker for Biogen, Novartis and Limbic Neurology. S.R.I. is supported by the Wellcome Trust (104079/Z/14/Z) and has received research funding from the UCB–Oxford University Alliance, BMA Research Grants — Vera Down (2013) and Margaret Temple (2017), Fulbright UK-US commission (MS Society research award), and Epilepsy Research UK (P1201). S.R.I. is a co-applicant on ‘Diagnostic Strategy to improve specificity of CASPR2 antibody detection’ (PCT/G82019 /051257) and receives royalties on a licenced patent application WO/210/046716 (PCT/GB2009/051441) entitled Neurological Autoimmune Disorders. S.R.I. has received honoraria from UCB, Immunovant, MedImmun, Roche, Cerebral therapeutics, ADC therapeutics, Brain and Medlink Neurology, and has received research support from CSL Behring, UCB and ONO Pharma. R.C.D. has received research funding from the Star Scientific Foundation, The Trish Multiple Sclerosis Research Foundation, Multiple Sclerosis Research Australia, the Petre Foundation and the NHMRC (Australia; Investigator Grant). He has also received honoraria from Biogen Idec as an invited speaker.

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Nature Reviews Neurology thanks J. Dalmau, A. McKeon and S. Vernino for their contribution to the peer review of this work.

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Ramanathan, S., Brilot, F., Irani, S.R. et al. Origins and immunopathogenesis of autoimmune central nervous system disorders. Nat Rev Neurol 19, 172–190 (2023). https://doi.org/10.1038/s41582-023-00776-4

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